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Acquired hemolytic anemia

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Acquired hemolytic anemia

  2. 2. ACQUIRED HEMOLYTIC ANEMIAS. Are mostly due to extra corpuscular or environmental changes.
  3. 3. Causes <ul><li>Hypersplenism (entrapment ) </li></ul><ul><li>Immune causes </li></ul><ul><ul><li>Warm reactive(IgG) antibody. </li></ul></ul><ul><ul><li>Cold reactive (IgM ) antibody (cold agglutinin disease) </li></ul></ul><ul><ul><li>Cold reactive (IgG) antibody. (paroxysmal cold hemoglobinuria) </li></ul></ul>
  4. 4. <ul><li>Drug dependent antibody. </li></ul><ul><ul><li>Auto immune. </li></ul></ul><ul><ul><li>Hapten. </li></ul></ul>
  5. 5. <ul><li>Traumatic hemolytic anemia. </li></ul><ul><ul><li>Impact hemolysis. </li></ul></ul><ul><ul><li>Macro vascular defects –Prostheses </li></ul></ul><ul><ul><li>Micro vascular causes. </li></ul></ul><ul><ul><ul><li>Thrombotic thrombocytopenic purpura. </li></ul></ul></ul><ul><ul><ul><li>Hemolytic uremic syndrome. </li></ul></ul></ul><ul><ul><ul><li>Disseminated intravascular hemolysis. </li></ul></ul></ul><ul><ul><ul><li>Other causes of microvascular abnormalities. </li></ul></ul></ul>
  6. 6. <ul><li>Hemolytic anemia due toxic effects on the membrane. </li></ul><ul><ul><li>Spur cell anemia </li></ul></ul><ul><ul><li>External toxins </li></ul></ul><ul><ul><ul><li>Animal or spider bites. </li></ul></ul></ul><ul><ul><ul><li>Metals (e.g.,copper) </li></ul></ul></ul><ul><ul><ul><li>Organic compounds. </li></ul></ul></ul><ul><li>Paroxysmal nocturnal hemoglobinuria. </li></ul>
  7. 7. HYPERSPLENISM <ul><li>sequestration of cells in the spleen causing cytopenia. </li></ul><ul><li>In the face of splenomegaly, there is increased destruction of the cells of the blood in a relatively nutrient poor environment full of phagocytic cells. </li></ul>
  8. 8. HYPERSPLENISM <ul><li>Normally 30% of total platelets are sequestered in the spleen and come out when needed if there is bleeding or infection </li></ul><ul><li>Normal spleen does not store or sequester RBC’s </li></ul><ul><li>Hypersplenism is characterised by </li></ul><ul><ul><li>Cytopenias </li></ul></ul><ul><ul><li>Splenomegaly </li></ul></ul><ul><ul><li>Hyperplastic Bonemarrow </li></ul></ul>
  9. 9. <ul><ul><li>Cytopenias result due to increased distruction of RBC, WBC & Platelets secondary to reduced flow of blood through enlarged and congested cords ( congestive splenomegaly ) or can be due to immune mediated mechanisms as the enlarged spleen has abundant phagocytes </li></ul></ul>
  10. 10. IMMUNE HEMOLYTIC ANEMIAS <ul><li>Auto immune hemolytic anemias.(AIHAs) </li></ul><ul><li>Due to antiboby production by the body against its own RBCs. </li></ul><ul><li>Characterised by a positive direct antiglobulin test (DAT) also known as the Coombs test. </li></ul><ul><li>Divided into warm and cold types according to whether the antibody reacts more strongly with red cells at 37 o c or 4 o c. </li></ul>
  11. 11. <ul><li>Warm antibody immuno hemolytic anemia </li></ul><ul><ul><li>these anbtibodies react at body temperature (37 o C) </li></ul></ul><ul><ul><li>Occurs at all ages. </li></ul></ul><ul><ul><li>More common in adult women. </li></ul></ul><ul><ul><li>25% of patients have an underlying lymphoid neoplasm. </li></ul></ul><ul><ul><li>The antibodies are nearly always IgG, rarely IgM or IgA. </li></ul></ul>
  12. 12. <ul><ul><li>May occur secondary to SLE where the RBCs are typically coated with IgG and C3 </li></ul></ul><ul><ul><li>When associated with ITP (auto immune thrombocytopenia) it is known as Evans syndrome. </li></ul></ul><ul><ul><li>It may occur as a result of some drugs which may stimulate antibody formation (eg., methyldopa) </li></ul></ul>
  13. 13. <ul><li>Mild form. </li></ul><ul><ul><li>Patients are asymptomatic. </li></ul></ul><ul><ul><li>Only there is a positive direct Coombs test. </li></ul></ul><ul><ul><li>There is insufficient antibody present on the RBC surface to permit the RE system to recognise the red blood cell as abnormal. </li></ul></ul>
  14. 14. <ul><li>Moderate form. </li></ul><ul><ul><li>Patients have moderate anemia. (Hb -6 to 10 gms% ) </li></ul></ul><ul><ul><li>Positive direct Coombs test. </li></ul></ul><ul><ul><li>Reticulocytosis of about 10 to 30%. </li></ul></ul><ul><ul><li>Spherocytosis. </li></ul></ul><ul><ul><li>Splenomegaly. </li></ul></ul><ul><ul><li>Venous thrombosis occasionally. </li></ul></ul>
  15. 15. <ul><li>Severe form. </li></ul><ul><ul><li>There is severe hemolysis associated with hemoglobinemia,hemoglobinuria and shock. </li></ul></ul><ul><ul><li>Rapidly fatal if not treated aggressively. </li></ul></ul>
  16. 16. COOMBS TEST. <ul><li>Major tool for diagnosing autoimmune hemolysis. </li></ul><ul><li>The direct coombs test detects IgG or C3 on the RBCs of the patient which indicates the presence of immune hemolysis </li></ul><ul><li>The coombs reagent may be broad spectrum or it may be specifically directed against IgG, IgM, IgA, or C3d (complement) </li></ul>
  17. 17. <ul><li>The test is positive if the RBCs agglutinate. </li></ul><ul><li>The antibodies both on the red cell surface and free in the serum are best detected at 37 o C. </li></ul><ul><li>Rarely neither IgG nor complement(C3) maybe found on the RBC of the patient (Coombs negative IHA) </li></ul>
  18. 19. WARM ANTIBODY IMMUNOHEMOLYTIC ANEMIA. <ul><li>Causes: </li></ul><ul><ul><li>Idiopathic. </li></ul></ul><ul><ul><li>Lymphomas </li></ul></ul><ul><ul><ul><li>Chronic lymphocytic leukemia </li></ul></ul></ul><ul><ul><ul><li>Non Hodgkins lymphoma </li></ul></ul></ul><ul><ul><ul><li>Hodgkins disease (infrequent) </li></ul></ul></ul><ul><ul><li>SLE and other collagen vascular diseases. </li></ul></ul><ul><ul><li>Drugs </li></ul></ul><ul><ul><ul><li>methyl dopa (autoantibody to Rh antigens) </li></ul></ul></ul><ul><ul><ul><li>Penicillin type(stable hapten) </li></ul></ul></ul><ul><ul><ul><li>Quinidine type(unstable hapten) </li></ul></ul></ul><ul><ul><li>Post viral infections. </li></ul></ul><ul><ul><li>Other tumors (rare) </li></ul></ul>
  19. 20. PATHOGENESIS <ul><li>In warm antibody IHA, the RBCs are usually coated with IgG alone or with complement and are therefore taken up by RE macrophages which have receptors for the IgFc fragment. </li></ul><ul><li>Part of the coated RBC membrane is lost and the cell becomes progressively more spherical to maintain the same volume and is ultimately destroyed prematurely in the spleen predominantly </li></ul><ul><li>When the cells are coated with IgG and complement or complement alone,RBC destruction occurs more generally in the RE system. </li></ul>
  20. 21. TREATMENT <ul><li>If mild hemolysis </li></ul><ul><ul><li>no treatment is required. </li></ul></ul><ul><ul><li>Remove the underlying cause. </li></ul></ul><ul><li>If significant hemolysis </li></ul><ul><ul><li>Treat with Prednisolone(1mg/kg/day) </li></ul></ul><ul><ul><li>Hb rises within 3 or 4 days and in most by 1 to 2 weeks. </li></ul></ul><ul><ul><li>Continue till Hb is risen to normal and then taper to 20mg/day and subsequently taper gradually. </li></ul></ul>
  21. 22. <ul><ul><li>Prednisolone acts by inhibiting the phagocytosis of the IgG coated RBC and by inhibiting antibody synthesis. </li></ul></ul><ul><li>Splenectomy </li></ul><ul><ul><li>in patients who fail to respond to prednisolone (spleen is the dominant site of RBC destruction ) </li></ul></ul>
  22. 23. <ul><li>Immunosuppressive therapy </li></ul><ul><ul><li>in those who fail to respond to prednisolone and splenectomy </li></ul></ul><ul><ul><li>Cyclophosphamide 100mg/day. </li></ul></ul><ul><ul><li>Azathioprine 150mg/day. </li></ul></ul><ul><ul><li>Rituximab 375mg/m2/week. </li></ul></ul>
  23. 24. <ul><li>Intravenous gamma globulin therapy. </li></ul><ul><li>May cause rapid cessation of hemolysis. </li></ul><ul><li>(not as effective as in immune thrombo </li></ul><ul><li>cytopenia-ITP) </li></ul>
  24. 25. <ul><li>Blood transfusion </li></ul><ul><ul><li>if severe anemia. </li></ul></ul><ul><ul><li>Warm antibody in IHA is a Panagglutinin. </li></ul></ul><ul><ul><li>This antibody reacts with all normal donor cells and hence compatible crossmatching is impossible. </li></ul></ul><ul><ul><li>Remove the autoantibody from patients serum and then test for the presence of alloantibody to donor blood groups. </li></ul></ul>
  25. 26. <ul><li>Prognosis </li></ul><ul><ul><li>AIHA is transient in children following viral infection. </li></ul></ul><ul><ul><li>Usually chronic in adults with exacerbations and remissions </li></ul></ul>
  26. 27. Warm AIHA
  27. 28. COLD ANTIBODY IMMUNOHEMOLYTIC ANEMIA. <ul><li>These antibodies are usually IgM and bind to red cells best at 4 o C and thus agglutinate RBC and are called cold agglutinins. </li></ul><ul><li>Uncommonly the antibody is IgG (Donath-Landsteiner antibody of paroxysmal cold hemoglobinuria) </li></ul>
  28. 29. <ul><li>Cold reacting autoantibodies </li></ul><ul><li>Are of 2 types </li></ul><ul><ul><li>Monoclonal </li></ul></ul><ul><ul><li>Polyclonal. </li></ul></ul><ul><li>Monoclonal </li></ul><ul><ul><li>these antibodies are the product of lymphoproliferative disorders </li></ul></ul><ul><ul><li>Also seen in idiopathic cold hemagglutinin syndrome. </li></ul></ul>
  29. 30. <ul><li>Polyclonal antibodies </li></ul><ul><ul><li>seen in response to infection as in Mycoplasma Pneumonia </li></ul></ul><ul><ul><li>Infectious mononucleosis. </li></ul></ul>
  30. 31. <ul><li>The antibodies attach to red cells mainly in the peripheral circulation where the blood temperature is cooled. </li></ul><ul><li>IgM antibodies are highly efficient at fixing complement and both intra and extravascular hemolysis can occur. </li></ul>
  31. 32. <ul><li>Cold agglutinins reacting against the I antigen on the red cell surface are called anti I. </li></ul><ul><li>These antibodies are seen in </li></ul><ul><ul><li>Mycoplasma infections </li></ul></ul><ul><ul><li>Benign lymphoproliferative disorders. </li></ul></ul>
  32. 33. <ul><li>Anti i antibodies react with fetal blood and are seen in </li></ul><ul><ul><li>Aggressive lymphomas </li></ul></ul><ul><ul><li>Infectious mononucleosis. </li></ul></ul>
  33. 34. CLINICAL FEATURES. <ul><li>Acrocyanosis. </li></ul><ul><li>Hemolysis. </li></ul><ul><li>Acrocyanosis </li></ul><ul><ul><li>marked purpling of the extremities,ears and nose when the blood becomes cold enough to agglutinate in the veins. </li></ul></ul><ul><li>Clears on warming and does not have vasospastic features. </li></ul><ul><li>Symptoms may be present when swallowing cold foods or drinks. </li></ul>
  34. 35. <ul><li>Hemolysis </li></ul><ul><ul><li>usually not severe with mild reticulocytosis and agglutination on the blood film. </li></ul></ul><ul><ul><li>occurs primarily due to the hemolytic action of the complement as there are no functional Fc receptors for the IgM antobody on the phagocytes. </li></ul></ul><ul><ul><li>Severe hemolysis occurs only with massive activation of the antibody(eg.,sudden cooling) </li></ul></ul>
  35. 36. <ul><ul><li>The activation of the complement is marked by accumulation of a degradation product of C3 called C3dg on the RBC surface which is detected with appropriate antisera(anti-C3) in the direct coombs test. </li></ul></ul>
  36. 37. COLD AIHA
  37. 40. PAROXYSMAL COLD HEMOGLOBINURIA <ul><li>Rare syndrome of intravascular hemolysis after exposure to cold. </li></ul><ul><li>Results from the formation of the Donath Landsteiner antibody an IgG antibody directed against the P blood group antigen and that can induce complement mediated lysis. </li></ul>
  38. 41. <ul><li>Attacks are precipated on exposure to cold and assoc with hemoglobinemia, hemoglobinuria, chills and fever, back, leg and abdominal pain, headache and malaise. </li></ul>
  39. 42. TREATMENT. <ul><li>Maintain patient in warm environment. </li></ul><ul><li>Splenectomy not of value. </li></ul><ul><li>Prednisolone of limited value. </li></ul><ul><li>Chlorambucil and cyclophoshamide for patients having hemollysis assoc with monoclonal gammopathy. </li></ul><ul><li>Rituximab(anti CD20) </li></ul><ul><li>Successful treatment of the neoplasm responsible for the cold agglutinin. </li></ul>
  40. 43. <ul><li>Recovery from acute episode is prompt. </li></ul><ul><li>Asymptomatic between episodes. </li></ul><ul><li>PCH usually secondary to a viral infection or are autoimmune. </li></ul><ul><li>PCH used to be more frequent with tertiary syphilis. </li></ul><ul><li>Following a viral infection (measles, mumps) it is self limited but maybe severe. </li></ul>
  41. 44. <ul><li>Direct coombs test may show complement (seldom IgG) but may be negative. </li></ul><ul><li>Diagnosis made by demonstrating cold reacting IgG antibodies or by special antiglobulin tests. </li></ul>
  42. 45. <ul><li>Chronic auto immune PCH may respond to prednisolone or cytotoxic therapy (azathioprine or cyclophosphamide) </li></ul><ul><li>Natural history of PCH extends over many years. </li></ul>
  43. 46. COLD ANTIBODY IMMUNOHEMOLYTC ANEMIA <ul><li>Cold agglutinin disease: </li></ul><ul><li>Acute </li></ul><ul><ul><li>mycoplasma infection </li></ul></ul><ul><ul><li>infectious mononucleosis </li></ul></ul><ul><li>Chronic </li></ul><ul><ul><li>Idiopathic </li></ul></ul><ul><ul><li>lymphoma. </li></ul></ul><ul><li>Paroxysmal cold hemoglobinuria. </li></ul><ul><li>Ulcerative colitis. </li></ul>
  44. 47. <ul><li>Transient Cold agglutinins occur commonly with mycoplasma pneumoniae infection and infectious mononucleosis </li></ul><ul><li>In both, the titer of antibody is too low to cause clinical symptoms of hemolysis ( antibody titer in symptomatic patients is usually about 1:2000 or more dilution) </li></ul><ul><li>Only rarely there is hemolysis </li></ul><ul><li>The presence of cold agglutinins is of diagnostic value </li></ul>
  45. 48. ALLOIMMUNE (ISOIMMUNE) HEMOLYTIC ANEMIAS <ul><li>In these hemolytic anemia's, the antibody produced by one individual reacts with red cells of another </li></ul><ul><li>Causes </li></ul><ul><ul><li>ABO incompatibility </li></ul></ul><ul><ul><ul><li>Transfusion of incompatible blood results in massive intravascular hemolysis and the blood film usually shows both autoagglutination and spherocytosis. </li></ul></ul></ul>
  46. 49. <ul><li>Hemolytic disease of the newborn </li></ul><ul><ul><li>Due to Rh incompatibility of the materno fetal blood groups. </li></ul></ul><ul><ul><li>The increased use of allogenic transplantation for renal, hepatic, cardiac and bone marrow diseases has led to the recognition of alloimmune hemolytic anemia resulting from the production of red cell antibodies in the recipient by donor lymphocytes transferred in the allograft. </li></ul></ul>
  47. 50. DRUG INDUCED IMMUNOHEMOLYTIC ANEMIA <ul><li>Drugs cause IHA by 2 different mechanisms: </li></ul><ul><ul><li>by inducing a disorder similar to warm antibody IHA(eg.,methyl dopa) </li></ul></ul><ul><ul><li>by becoming associated as haptens with RBC surface and induce the formation of an antibody against RBC-drug complex(eg.,penicillin, quinidine) </li></ul></ul>
  48. 51. <ul><li>With methyl dopa: </li></ul><ul><ul><li>10% of patients taking 2g/day usually show a positive direct coombs test. </li></ul></ul><ul><ul><li>Few may show spherocytosis and hemolysis. </li></ul></ul><ul><ul><li>The autoantibodies crossreact with Rh protein. </li></ul></ul><ul><ul><li>The autoantibody may persist for many months after the drug is discontinued. </li></ul></ul>
  49. 52. <ul><ul><li>The hemolytic reaction continues until the drug has been discontinued. </li></ul></ul><ul><ul><li>Penicillin and its congeners cause this type of reaction when given in high doses(10 million units/day or more) </li></ul></ul><ul><ul><li>The direct coombs test is positive only with anti IgG. </li></ul></ul><ul><ul><li>The indirect coombs test is positive only when the normal RBCs are coated with penicillin </li></ul></ul>
  50. 53. <ul><ul><li>Complement is not usually fixed. </li></ul></ul><ul><ul><li>Hemolysis is usually not severe. </li></ul></ul><ul><ul><li>As the antibody is of IgG type,spherocytosis and splenic destruction may occur. </li></ul></ul><ul><ul><li>Other drugs like quinine,quinidine, sulfonamides, sulfonylureas, phenacetin etc do not adhere tightly to the RBC surface and the drug antibody complexes are removed during the washing steps of the coombs reactions. </li></ul></ul>
  51. 54. <ul><li>These IgM antibodies are able to fix complement and C3d and C4d remain on the RBC surface. </li></ul><ul><li>Therefore the direct coombs test is positive with anti C3 but not with anti IgG. </li></ul><ul><li>The antibody is detected in the indirect coombs test only when the drug is added to the incubation mixture. </li></ul><ul><li>Hemolysis may be severe and resolves once the drug is discontinued. </li></ul>
  52. 56. PowerPoint* Lecture slide Presentation By Dr.P.L.John Israel , Professor & Head of the Department of Internal Medicine Prathima Institute of Medical Sciences, Nagunur-Karimnagar Dist. Andhra Pradesh - INDIA HEMOLYTIC ANAEMIA THANK YOU ACQUIRED
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