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1. Clinical Laboratory Hematology, Third Edition Shirlyn B. McKenzie | J. Lynne Williams Immune Hemolytic Anemia 2. Clinical Laboratory Hematology, Third Edition Shirlyn B. McKenzie | J. Lynne Williams Introduction Immune hemolytic anemia (IHA) RBCs destroyed prematurely by immune process mediated by antibody and/or complement Presence and severity of anemia depends on: Severity of hemolysis Ability of BM to compensate for RBC loss continued on next slide 3. Clinical Laboratory Hematology, Third Edition Shirlyn B. McKenzie | J. Lynne Williams Introduction Immune hemolytic anemia (IHA) Initial confirmation of immune mechanism Demonstration of attachment of Ab or complement to RBCs of patient Diagnosis of anemia: Hb and Hct, reticulocytes and/or unconjugated bilirubin, haptoglobin 4. Clinical Laboratory Hematology, Third Edition Shirlyn B. McKenzie | J. Lynne Williams Classification of IHAs Based on stimulus for antibody production Autoimmune hemolytic anemia Drug-induced hemolytic anemia Alloimmune hemolytic anemia Important to determine process because each type requires specific treatment 5. Clinical Laboratory Hematology, Third Edition Shirlyn B. McKenzie | J. Lynne Williams Classification Autoimmune hemolytic anemia (AIHA) Shortened RBC survival Caused by production of autoantibodies against RBC antigens Ab-induced reactions include Sensitization, agglutination, hemolysis continued on next slide 6. Clinical Laboratory Hematology, Third Edition Shirlyn B. McKenzie | J. Lynne Williams Classification Autoimmune hemolytic anemia (AIHA) Further classified Warm-antibody autoimmune HA (WAIHA) Cold-antibody AIHA (cold agglutinin disease/CAD) Mixed-type AIHA (both warm-reacting and cold-reacting autoantibodies) 7. Clinical Laboratory Hematology, Third Edition Shirlyn B. McKenzie | J. Lynne Williams Table 19-1 Classification of Immune Hemolytic Anemias 8. Clinical Laboratory Hematology, Third Edition Shirlyn B. McKenzie | J. Lynne Williams Table 19-2 Characteristics of Agglutinins in Hemolytic Anemia 9. Clinical Laboratory Hematology, Third Edition Shirlyn B. McKenzie | J. Lynne Williams Classification Drug-induced hemolytic anemia Drugs attach to RBC membrane or alter it. Classified based on reactions of patient's RBCs and drug in vitro test system Drug-dependent Drug-independent 10. Clinical Laboratory Hematology, Third Edition Shirlyn B. McKenzie | J. Lynne Williams Classification Alloimmune hemolytic anemia Antibody (Ab) development to RBC antigen (Ag) that individual lacks Do not react with individual's own RBCs HDFN-mother makes Abs against Ags on fetal RBCs Transfusion reactions where recipient makes Abs to Ags on transfused (donor cells) 11. Clinical Laboratory Hematology, Third Edition Shirlyn B. McKenzie | J. Lynne Williams Sites and Factors that Affect Hemolysis Intravascular or extravascular hemolysis Depends on: Class of Ab Ability to fully activate complement cascade continued on next slide 12. Clinical Laboratory Hematology, Third Edition Shirlyn B. McKenzie | J. Lynne Williams Sites and Factors that Affect Hemolysis Intravascular or extravascular hemolysis Extravascular hemolysis Most common RBC sensitized with Ab or complement Sensitized cells phagocytized by macrophages in spleen or liver continued on next slide 13. Clinical Laboratory Hematology, Third Edition Shirlyn B. McKenzie | J. Lynne Williams Sites and Factors that Affect Hemolysis Intravascular or extravascular hemolysis Intravascular hemolysis Complement cascade activated C9 (MAC) RBC lysis 14. Clinical Laboratory Hematology, Third Edition Shirlyn B. McKenzie | J. Lynne Williams Figure 19-1 Immune-mediated extravascular hemolysis. Erythrocytes sensitized with antibody or complement (C3b) attach to macrophages via specific cell receptors for these immune proteins. 15. Clinical Laboratory Hematology, Third Edition Shirlyn B. McKenzie | J. Lynne Williams Table 19-3 Factors Affecting the Rate of Hemolysis in Immune Hemolytic Anemias 16. Clinical Laboratory Hematology, Third Edition Shirlyn B. McKenzie | J. Lynne Williams Mechanisms of Hemolysis Based on whether IgM, IgG, and/or complement are present on RBC Three types: IgG-mediated Complement-mediated IgM-mediated 17. Clinical Laboratory Hematology, Third Edition Shirlyn B. McKenzie | J. Lynne Williams IgG-Mediated Hemolysis IgG attaches to RBC membrane Ags via Fab region. Fc receptors FcR-I, -II, -III on macrophages of spleen Bind to Fc portion of Ab attached to RBC Macrophage pits the Ag/Ab complex continued on next slide 18. Clinical Laboratory Hematology, Third Edition Shirlyn B. McKenzie | J. Lynne Williams IgG-Mediated Hemolysis Fc receptors Damages RBC membrane RBC membrane reseals itself Repeated splenic passagecontinues to lose membrane, forms spherocyte Phagocytized by splenic macrophages 19. Clinical Laboratory Hematology, Third Edition Shirlyn B. McKenzie | J. Lynne Williams IgG-Mediated Hemolysis Ab-sensitized RBCs can be entirely engulfed by: Macrophages PMN (FcR-I, -III) NK cells (FcR-III)results in ADCC (Ab dependent cell-mediated cytotoxicity) 20. Clinical Laboratory Hematology, Third Edition Shirlyn B. McKenzie | J. Lynne Williams IgG-Mediated Hemolysis Spleen Lightly opsonized cells more efficiently removed Liver Removes heavily sensitized cells Splenomegaly is common 21. Clinical Laboratory Hematology, Third Edition Shirlyn B. McKenzie | J. Lynne Williams Complement-Mediated Hemolysis Role of complement Sensitization Only portion of complement cascade activated and deposited on RBC membrane Lysis of RBCs Entire complement system activated and deposited on RBC membrane 22. Clinical Laboratory Hematology, Third Edition Shirlyn B. McKenzie | J. Lynne Williams Complement-Mediated Hemolysis Initiation of complement activation Classic, alternate, lectin mechanisms Classic pathway Initiated by Ag/Ab reaction IgM Activates complement more efficiently Only requires one IgM molecule IgG (IgG1 and IgG3; occasional IgG2) Activation requires two IgG molecules 23. Clinical Laboratory Hematology, Third Edition Shirlyn B. McKenzie | J. Lynne Williams Complement-Mediated Hemolysis Cascade initiated C1 binds to the Fc region of IgG or IgM. Activates C4, C2, C3 Activates the terminal components C5 to C9 Membrane attack complex (MAC) Lytic attack to RBC membrane Intravascular hemolysis when complement activation C1C9 is complete continued on next slide 24. Clinical Laboratory Hematology, Third Edition Shirlyn B. McKenzie | J. Lynne Williams Complement-Mediated Hemolysis Cascade initiated Activations through C3 RBC sensitized with C3b Totally or partially engulfed by macrophages with receptors for C3b C3b on RBC cleaved by plasma C3b inactivator C3c dissociates from membrane. C3d no receptors on macrophages Normal RBC survival 25. Clinical Laboratory Hematology, Third Edition Shirlyn B. McKenzie | J. Lynne Williams Figure 19-2 The complement cascade. The central event in complement activation is the activation of C3 by C3 convertases. This can occur by two separate but interrelated mechanisms, the classic and alternate pathways. The classic complement pathway is initiated by an antigenantibody reaction. The antigenantibody complex activates the C1q, r, s complex, which in turn activates C4 by proteolytic cleavage to C4a and C4b. C2 binds to C4b and is proteolytically cleaved by C1s to form C2a and C2b. The C4b2a complex serves as C3 convertase. In the alternate pathway, C3b serves as the cofactor of the C3-cleaving enzyme complex (C3b, P, Bb), also known as C3 convertase. Thus, C3b serves to prime its own activation. The C3b formed through the classic pathway can directly initiate the assembly of the alternate pathway C3 convertase. C3 can also be activated by spontaneous hydrolysis. The C3b complexes formed by the classic and alternate pathways activate C5 to C5a and C5b. Membrane damage is initiated by the assembly of C5b with C6, 7, 8, 9. 26. Clinical Laboratory Hematology, Third Edition Shirlyn B. McKenzie | J. Lynne Williams IgM-Mediated Hemolysis Macrophages do not have receptors for Fc portion of IgM. IgM is efficient activator of complement Intravascular Complement activation through C9 and RBC hemolyzes continued on next slide 27. Clinical Laboratory Hematology, Third Edition Shirlyn B. McKenzie | J. Lynne Williams IgM-Mediated Hemolysis Macrophages do not have receptors for Fc portion of IgM. IgM is efficient activator of complement. Extravascular Activation incomplete C3b coats RBCs and sensitized cells destroyed extravascularly via CR1 and CR3 receptors on macrophages. IgM can agglutinate cells in addition to activating complement. 28. Clinical Laboratory Hematology, Third Edition Shirlyn B. McKenzie | J. Lynne Williams Laboratory ID of Sensitized RBCs Two agglutination techniques Salinedetects IgM antibodies AHG testdetects IgG and/or complement Direct AHG (DAT) Detects RBCs coated in vivo Required to differentiate AIHA from other types of HA continued on next slide 29. Clinical Laboratory Hematology, Third Edition Shirlyn B. McKenzie | J. Lynne Williams Laboratory ID of Sensitized RBCs Two agglutination techniques AHG testdetects IgG and/or complement Indirect AHG (IAT) Detects antigens in plasma or serum (in vitro) Indicates alloimmunization or free autoAbs in patient's serum 30. Clinical Laboratory Hematology, Third Edition Shirlyn B. McKenzie | J. Lynne Williams Figure 19-3 The zeta potential of erythrocytes keeps the cells about 25 nm apart when suspended in saline. IgG antibodies have a span of about 14 nm, not enough to bridge the gap between cells and cause agglutination. IgM antibodies, however, are pentamers with a span of about 35 nm, a distance sufficient to bridge the space between cells and cause agglutination. 31. Clinical Laborato

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