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AUTO IMMUNE HEMOLYTICANEMIA
Dr. DEVESH A. TIWARIPediatric Hematology Oncology
LTMMC & GH
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Autoimmune Hemolytic Anemia
Immune mediated HemolyticAnemia
Immunologic destruction of RBCsmediated by autoantibodiesagainst antigens on the RBCsurface
Classified by isotype (IgG, IgM,IgA) and temperature.
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CLASSIFICATION
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Pathogenesis of AutoAb Formation
AutoAbs polyclonal B Lymphocyte response
Variety of T lymphocyte AbNs.
Role of Macrophages n Monocytes
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IMMUNE HEMOLYTIC ANEMIA
General 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
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IMMUNE HEMOLYTIC ANEMIAGeneral Principles - 2
Antibodies combine with RBC, & either
1. Activate complement cascade, &/or
2. Opsonize RBC for immune system
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If 1, if all of complement cascade isfixed to red cell, intravascular cell lysisoccurs
If 2, &/or if complement is only
partially fixed, macrophages recognizeFc receptor of Ig &/or C3b ofcomplement & phagocytize RBC,causing extravascular RBC destruction
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Pathophysiology of Hemolysis
Mainly by immunoadherence mediated indirect lysisresulting in extravascular hemolysis by phagocytic cells(spherocytes, elevated LDH/bili)
Complement-mediated direct lysis resulting inintravascular hemolysis (hemoglobinemia,
hemoglobinuria, hemosiderinuria)
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Severity of hemolysis
Amount of hemolysis depends upon:
Antibody titer ( the higher the titer, themore hemolysis)
Thermal amplitude
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AUTOIMMUNE HEMOLYSIS
Warm 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
Responsive to steroids/splenectomy
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Cold-Induced Hemolysis Two different clinical entities due to
cold-reacting antibodies:
Cold Agglutinin disease
Paroxysmal cold hemoglobinuria
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AUTOIMMUNE HEMOLYSIS
Cold Type
Most commonly IgM mediated
Antibodies bind best at 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
Poorly responsive to steroids, splenectomy;responsive to plasmapheresis
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Cold Agglutinin Disease
IgM Autoantibodies (rarely IgA or IgG) directedagainst polysaccharide antigens (anti-I or i) onthe RBC surface
Found frequently in normal adults at low titers
Pathology results with high titer antibodyproduction:
Oligoclonal antibodies due to infection
Monoclonal antibodies due to paraneoplastic orneoplastic process
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Associated Infections
Mycoplasma pneumoniae (anti-I) 50-75%
Infectious mononucleosis (anti-i) 60%
Other viruses: CMV, Varicella, Rubella,Parvovirus B19, Hepatitis B, HIV, Influenza B
Listeria monocytogenes (anti-I)
Other bacteria: Legionella pneumophila,Chlamydia psittacosis
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Monoclonal Cold Agglutinins
Paraneoplastic or neoplastic growth of animmunocyte clone
Kappa light chain anti-I antibodies
CLL, Waldenstroms macroglobulinemia, lymphocyticlymphoma
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Clinical & Laboratory Findings
WAIHA Pallor Palpitations
Dyspnea, Exercise Intolerance Mild Icterus Moderate splenomegaly Positive DAT
Microspherocytes Polychromasia nRBCs (K retic count) K bilirubin (unconjugated)
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Chronic CAD
Clinical manifestations similar to WAIHA Raynauds phenomena sometimes reported Pallor and cyanosis of extremities
Acute CAD 2 to infection (Mycoplasma pneumoniae) Severe hemolysis Positive DAT PolychromasiaAutoagglutination of RBCs interferes with
automated cell counters
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Reticulocyte Manual Count by
Supravital Stain
Normal Count Elevated Count
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DIAGNOSIS
DAT (DCT)
Most important & useful Lab
test
Identifies Abs &complement components onthe surface of circulatingRBCs
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Looks for immunoglobulin &/or complementof surface of red blood cell (normally neither
found on RBC surface)
Coombs reagent - combination of anti-human
immunoglobulin & anti-human complement
Mixed with patients red cells; ifimmunoglobulin or complement are on
surface, Coombs reagent will link cellstogether and cause agglutination of RBCs
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DIAGNOSIS
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Coombs Test - Indirect
Looks foranti-red bloodcell antibodies inthe patients serum, using a panel ofredcells with knownsurface antigens
Combine patientsserumwith cells fromapanel of RBCswith knownantigens
AddCoombsreagenttothismixture
If anti-RBCantigensare inserum,agglutinationoccurs
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Differential Diagnosis
1. Anti-IgG Positive + Anti-C3 Negative -
Idiopathic Warm AIHA, Drug induced warm AIHA(penicillin, methyldopa)
2. Anti-IgG Positive + Anti-C3 Positive +
SLE, idiopathic warm AIHA, rarely drug associated
3. Anti-IgG Negative - Anti-C3 Positive + Cold agglutinin disease, Paroxysmal cold
hemoglobinuria, rarely warm AIHA if low-affintiy IgG
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THERAPY
PRC transfusion STEROIDS
IVIG
PLASMAPHARESIS Splenectomy
Danazol (50 100 mg/day)
IS : VCR 1mg/m2, Azathioprine 25-200mg/d, Cyclophosphamide 50-100mg/d, CsA, Rituximab 375mg/m2iv/wk
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Risk of transfusion1. Presence of the autoantidody complicates pretransfusion testing and may
prevent accurate identification of coexisting alloantibodies2. Autoantibody itself may cause decreased survival of transfused cells
worsening hemolysis and clinical deterioration
Decision making1. Patients clinical status 2. Potential benefit of transfusion
3. Potential response to other therapeutic modalities
4. Status of the serologic evaluation and pretransfusion testing
Severe but
stable anemia
steroid therapy
Chronic stable
Anemia (poor response toimmunosuppressivetherapy)
Acute fulminant hemolysis
or progressively severe anemiaCardiac or cerebral dysfunction
Periodic transfusion Urgent transfusion
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IMMUNE HEMOLYSIS
Drug-Related
Immune Complex Mechanism
Quinidine, Quinine, Isoniazid
Haptenic Immune Mechanism
Penicillins, Cephalosporins
True Autoimmune Mechanism
Methyldopa, L-DOPA, Procaineamide,Ibuprofen
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DRUG-INDUCED HEMOLYSIS
Immune Complex Mechanism
Drug & antibody bind in the plasma
Immune complexeseitherActivate complementin the plasma, or
Siton red blood cell
Antigen-antibody complex recognized by REsystem
Red cellslysed asinnocent bystander ofdestructionofimmune complex
REQUIRES DRUG IN SYSTEM
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DRUG-INDUCED HEMOLYSIS
HaptenicMechanism
Drug bindsto & reactswith red cell
surface proteinsAntibodies recognize altered protein,
drug, as foreign
Antibodiesbind to altered protein&initiate process leading to hemolysis
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DRUG-INDUCED HEMOLYSIS
True AutoantibodyFormation
Certaindrugs appeartocauseantibodies thatreactwith antigensnormally foundonRBC surface, anddosoeveninthe absence ofthe drug
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HEMOLYTIC ANEMIA
Summary Myriad causes of increased RBC
destruction
Marrow function usuallynormal Often requires extra folic acid tomaintain hematopoiesis
Anything that turns off the bone
marrow can result in acute, life-threatening anemia
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THANK YOU
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