DEVESH AIHA

8/8/2019 DEVESH AIHA

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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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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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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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DEVESH AIHA